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Crystal form of gemcitabine predrug, preparation method and use of crystal form and pharmaceutical composition

A gemcitabine and composition technology, which is applied in the directions of drug combination, pharmaceutical formula, sugar derivative preparation, etc., can solve the problems of stability and bioavailability difference, affecting drug efficacy, etc., and achieves stable curative effect, easy automatic control, and convenient operation. Effect

Inactive Publication Date: 2017-07-14
TETRANOV PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

The crystal form is the solid state in which the drug exists. The study of the drug crystal form is the study of the basic state of the drug. Only with a full and comprehensive understanding of the chemical drug crystal form can it be possible to find a more suitable drug crystal for the treatment of diseases. It is well known that different crystal forms of the same drug have significant differences in their stability and bioavailability, thereby affecting the efficacy of the drug. At present, there are no reports at home and abroad on how to obtain the crystal form of the compound shown in formula (I)

Method used

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  • Crystal form of gemcitabine predrug, preparation method and use of crystal form and pharmaceutical composition
  • Crystal form of gemcitabine predrug, preparation method and use of crystal form and pharmaceutical composition
  • Crystal form of gemcitabine predrug, preparation method and use of crystal form and pharmaceutical composition

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preparation example Construction

[0044] 1. Preparation of gemcitabine prodrug compound

[0045] In a specific embodiment, the gemcitabine prodrug (Formula I) used is prepared by referring to the methods in the patent CN102532199 and the journal paper J.Med.Chem.2016, 59, 3661-3670. Its specific preparation method is as follows, but not limited to this method:

[0046] synthetic route:

[0047]

[0048] Synthesis of compound b: 8.8g (33.5mmol) of compound a was dissolved in 200ml of DMF, 6.8g (100.5mmol) of imidazole and 5.1ml (36.9mmol) of triethylamine were added thereto, and then TBSCl was added in batches under ice-cooling 12.7g (83.8mmol), after the addition, naturally rise to room temperature and react overnight. TLC monitors that the basic reaction is complete. Add saturated aqueous ammonium chloride solution to the system to quench the reaction, extract three times with ethyl acetate (EA), combine the organic phases, wash five times with saturated brine, dry over anhydrous sodium sulfate, spin dr...

Embodiment 1

[0057] The gemcitabine prodrug crystal form of the present embodiment is the gemcitabine prodrug crystal form shown in formula I, and its preparation method is as follows: get 4.4g gemcitabine prodrug solid dispersion as shown in formula I into 800mL ethyl acetate and 8mL isopropanol In the mixed solvent, heated to 95°C and refluxed for 1h, the solids were completely dissolved, then cooled down by 10°C per hour to 15°C, stood still for 15h to precipitate crystals, collected the filter cake by filtration, and dried at 30°C to obtain 1.5g Solid, ready to serve.

[0058] The crystals prepared in this example were subjected to X-ray powder diffraction measurement under the following conditions: operating voltage 35KV, tube current 30mA, angle range: 2-40°, step size: 0.01° / step, wavelength 1.5406. Its X-ray diffraction pattern is as figure 1 The more detailed parameters are shown in Table 1.

[0059] The XRD peak value of the gemcitabine prodrug crystal form shown in table 1 for...

Embodiment 2

[0064] The gemcitabine prodrug crystal form of the present embodiment is the gemcitabine prodrug crystal form shown in formula I, and its preparation method is as follows: get 0.4g gemcitabine prodrug solid dispersion as shown in formula I into 60mL ethyl acetate and 2mL isopropanol In the mixed solvent, heated to 80°C and refluxed for 2 hours, the solids were completely dissolved, and the temperature was lowered by 10°C per hour to 15°C, and the crystals were precipitated after standing for 10 hours, the filter cake was collected by filtration, and dried at 30°C to obtain 0.2g Solid, ready to serve.

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Abstract

The invention relates to a compound crystal form, a preparation method and use thereof and a pharmaceutical composition and particularly relates to a crystal form of a gemcitabine predrug, a preparation method and use of the crystal form and an anti-cancer pharmaceutical composition containing the crystal form of the gemcitabine predrug. The crystal form is a crystal form of the gemcitabine predrug represented by a formula I (shown in the description), and an X-ray powder diffraction pattern of the crystal form has a characteristic peak when a diffraction angle 2theta is 6.30+ / -0.2 degrees, 8.88+ / -0.2 degrees, 9.15+ / -0.2 degrees, 12.52+ / -0.2 degrees, 14.85+ / -0.2 degrees, 15.86+ / -0.2 degrees, 17.24+ / -0.2 degrees, 17.66+ / -0.2 degrees, 18.26+ / -0.2 degrees, 20.37+ / -0.2 degrees, 21.74+ / -0.2 degrees, 22.14+ / -0.2 degrees and the like. The invention further discloses the preparation method of the crystal form of the gemcitabine predrug, use of the crystal form for preparation of anti-cancer drugs and the anti-cancer pharmaceutical composition containing the crystal form of the gemcitabine predrug.

Description

technical field [0001] The present invention relates to a crystal form, a preparation method, an application and a pharmaceutical composition of a compound, in particular to a crystal form, a preparation method, an application and an anticancer pharmaceutical composition of a gemcitabine prodrug. Background technique [0002] Gemcitabine (Gemcitabine) is a difluoronucleoside antimetabolite anticancer drug that destroys cell replication. Break, play a cytotoxic effect to produce drug effect (Journal of Clinical Oncology 2006, 11, 828-829; Journal of Second Military Medical University 2006, 27, 1154-1156). The FDA approved it as a first-line drug for pancreatic cancer, which can significantly improve the quality of life and prolong the survival of patients with pancreatic cancer (Annals of Oncology 1996, 7, 347-353; Journal of Clinical Oncology 1997, 15, 2403-2413). The gold standard for pancreatic cancer treatment. Gemcitabine has a broad anti-tumor spectrum and has a certa...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H1/06A61K31/7068A61P35/00
CPCC07H19/10C07B2200/13C07H1/06
Inventor 吴豫生牛成山梁阿朋韩兴旺郭瑞云李敬亚邹大鹏
Owner TETRANOV PHARMA CO LTD
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